Clinical Features and Management of Acquired Resistance to PD-1 Axis Inhibitors in 26 Patients With Advanced Non–Small Cell Lung Cancer

doi:10.1016/j.jtho.2018.03.008

Journal of Thoracic Oncology

Volume 13, Issue 6, June 2018, Pages 831-839

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Abstract

Introduction

With expanding indications for programmed death 1 (PD-1) axis inhibitors in non–small cell lung cancer (NSCLC), acquired resistance (AR) to these therapies is increasingly being encountered. We sought to characterize clinical patterns of AR to PD-1 axis inhibitors in patients with advanced NSCLC, and evaluate subsequent outcome and management strategies for such patients.

Methods

Patients with NSCLC who developed AR to PD-1 axis inhibitor therapy initiated between December 2009 and February 2016 at one institution were identified and examined by clinical and radiographic features. AR was defined as progressive disease after initial response by either Response Evaluation Criteria in Solid Tumors v1.1 or immune-related response criteria.

Results

Twenty-six patients with AR to PD-1 axis inhibitor therapy were identified and evaluated. Median time to AR was 313 days; the 2-year survival rate from AR was 70% (95% confidence interval: 0.53–0.92). Twenty patients (77%) experienced AR in lymph nodes (LNs), including 11 patients with LN-only progression. Twenty-three (88%) patients had recurrence limited to one (54%) or two (35%) sites of disease. Fourteen patients (54%) continued PD-1 axis inhibitor therapy beyond progression. Three patients were re-challenged with the same PD-1 axis inhibitor after holiday from and progression off therapy, 2 again responded. Fifteen patients (58%) received local therapy to site(s) of AR, 11 continued respective PD-1 axis inhibitor after local therapy. The 2-year survival rate from AR among these 15 patients was 92% (95% confidence interval: 0.77–1).

Conclusions

Acquired resistance to PD-1 axis inhibitors is often limited to one or two sites when local therapy and continuation of PD-1 axis inhibitor therapy can result in prolonged benefit. LN metastases appear to be particularly susceptible sites to AR. When progression of disease following response occurs after holiday from PD-1 axis inhibitor, re-challenge can again lead to tumor regression.

Keywords

PD-1

PD-L1

acquired resistance

non–small cell lung cancer

immunotherapy

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: Disclosures: Dr. Gettinger has received consulting fees from Bristol-Myers Squibb, Alexion, and ARIAD/Takeda; and has received research funding from Bristol-Myers Squibb, Genentech, and Celldex. Dr. Goldberg has received grants from Astra Zeneca; and has received personal fees from Astra Zeneca, Bristol-Myers Squibb, Lilly, and Boehringer Ingelheim. Dr. Rimm has received personal fees from Astra Zeneca, Bristol-Myers Squibb, and Merck; and has received research funding from Astra Zeneca and Navigate/Novartis. Dr. Schalper has received research funding from Genoptix (Novartis), Tesaro, and Vasculox. Dr. Kaech has received research funding from Roche and Astra Zeneca. Dr. Chiang has received consulting fees from Astra Zeneca. Dr. Lilenbaum has received consulting fees from Genetech and Astra Zeneca. Dr. Politi has received consulting fees from Astra Zeneca, Novartis, Merck, and Tocagen; and has received royalties as co-investigator on a patent for Molecular MD/MSKCC; and has received grants from Astra Zeneca, Roche, Koltan, and Symphogen. Dr. Herbst has received consultant fees from Merck, Bristol-Myers Squibb, Astra Zeneca, Genentech/Roche, Pfizer, and Eli Lilly; and has received grants from Genentech/Roche and Merck. The remaining authors declare no conflicts of interest.